menopause: clustering of metabolic syndrome components and population changes in insulin resistance

Menopause: clustering of metabolic syndromecomponents and population changes in insulinresistanceM. Lejskova, S. Alusık, M. Suchanek*, S. Zecova and J. Pitha{

Department of Medicine, Thomayer Teaching Hospital, Prague; *Institute of Chemical Technology, Department of AnalyticalChemistry, Prague; {Institute of Clinical and Experimental Medicine, Laboratory of Atherosclerosis Research, Prague, Czech Republic

Key words: MENOPAUSE, METABOLIC SYNDROME, CENTRAL OBESITY, INSULIN RESISTANCE, CARDIOVASCULAR DISEASE, DYSLIPIDEMIA,

BLOOD PRESSURE

ABSTRACT

Aim The incidence of the metabolic syndrome (MS) in women rises rapidly during the menopause,

substantially increasing their cardiovascular risk and mortality. The aim of the study was to analyze

menopausal changes in individual MS components and the parameter of insulin resistance (HOMA-IR).

Methods A random population sample of 909 women aged 45–54 years, resident in Prague 4, was examined in

an epidemiological study. After excluding women with gynecological hormone therapy or surgical therapy, the two

groups of women were compared: women of reproductive age (REPRO, n¼ 245) vs. naturally postmenopausal

women (POSTm, n¼ 149).

Results The incidence of MS rose significantly in menopause (REPRO/POSTm 22.9+2.6%/38.3+4.0%;

p50.001). However, a detailed analysis among the five components defining MS showed that increases were only

seen in waist circumference (p50.0001) and triglycerides (p50.001). There was no increase in the other

components or HOMA-IR. A detailed analysis showed an increase in HOMA-IR at levels above the median

(REPRO/POSTm: low HOMA-IR 0.9/0.9, not significant; high HOMA-IR 1.8/2.1, p50.001) and an increase in

the incidence of MS just in these high levels of HOMA-IR and those rising during menopause (REPRO/POSTm:

low HOMA-IR 13.8%/18.7%, not significant; high HOMA-IR 30.9%/57.3%, p50.0001). In menopause, there

was an increase in the clustered incidence (accompanying MS) of each of the five MS components at the expense of

isolated incidence (not accompanying MS).

Conclusion The acceleration of MS incidence at the onset of menopause may be accompanied by an increase

in insulin resistance only in the population at highest risk. Reproductive women entering the menopause with

an isolated MS component are at high risk for developing additional risk factors during menopause.

INTRODUCTION

The cardiovascular risk of women of child-bearing potential is

known to be low compared with that of age-matched men.

After menopause, the cardiovascular risk of women quickly

rises and, overall, more women than men die of cardiovas-

cular disease in the industrialized nations1–3. This increased

risk was believed to be caused by hypercholesterolemia due to

the loss of production of ovarian estrogen. According to recent

studies, the increase in cardiovascular risk is also due to a rise

in androgenic effects associated with adipose tissue redis-

tribution in favor of abdominal obesity and accelerated

incidence of the metabolic syndrome (MS, Table 1) already

during the menopausal transition4–7. Among the five compo-

nents of MS, it is particularly central obesity where increases

beyond those due to aging can already be seen during the

menopausal transition. A similar increase has been reported in

serum triglyceride levels in most studies. Data regarding

increases in blood pressure, fasting glucose and insulin

resistance and a decrease in high density lipoprotein (HDL)

cholesterol beyond those associated with aging are contro-

versial8–18.

Correspondence: Dr M. Lejskova, Department of Medicine, Thomayer Teaching Hospital, Vıdenska 800, 14021 Prague, Czech Republic

CLIMACTERIC 2011;14:83–91

ORIGINAL ARTICLEª 2011 International Menopause SocietyDOI: 10.3109/13697131003692745

Received 11-08-2009Revised 06-12-2009

Aceepted 07-02-2010

Clim

acte

ric

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/28/

14Fo

r pe

rson

al u

se o

nly.

The aim of our population-based study was therefore to

clarify the rapid rise in the incidence of MS during the

menopausal transition that is not associated with a significant

deterioration in insulin resistance or a significantly increasing

incidence of some of its components. The Czech population is

a suitable model for studying MS prevalence, as it is one of the

most obese populations in Europe19 and at high risk.

METHODS

Study design

The study was conducted in 2003–2005, with a 5% random

representative sample of women aged 45–54 years selected

using a registry of women with permanent residence in Prague

4 district. Those selected were invited in writing to visit a

specialist clinic in Prague 4. The study protocol was approved

by the Institutional Ethics Committee with informed consent

obtained from all participants. A total of 909 women

(response rate, 64%) attended the examination.

Complete data were obtained from a total of 862 women

(mean age 50.0+2.7 years). After excluding 267 women with

surgically induced menopause or those with gynecological

hormone therapy, there were 595 women with a natural

course of the perimenopausal period (Figure 1). Using the

Stages Reproductive Aging Workshop (STRAW20,21) criteria,

the 595 women were divided into one of the three following

subgroups: ‘reproductive women’ (REPRO: 245 women,

regular menstrual cycles, fewer than 33 postmenstrual days),

‘perimenopausal women’ (201 women, irregular menstrual

cycles and/or 33–365 postmenstrual days; this group was not

included in this analysis), and ‘postmenopausal women’

(POSTm: 149 women, more than 365 postmenstrual days).

Naturally postmenopausal women (POSTm) had high levels

of follicle stimulating hormone (FSH), consistent with the

postmenopausal status. Increased levels of FSH, 430 mU/ml

and 440 mU/ml, were seen in 94.6% and in 91.9% of

women of this group, respectively. The remaining eight

postmenopausal women had a mean time from the last

menstruation of 3.9 years, similar to the mean of the entire

POSTm group (4.4 years). Women in the REPRO and POSTm

subgroups were compared in the study.

Definitions

To evaluate the menopausal transition, the self-reported

characteristic of menstruation using the STRAW criteria was

used20,21. The study used the MS definition according to criteria

recommended by the International Diabetes Federation (IDF)

Table 1 Metabolic syndrome according to the definition of the

International Diabetes Federation22

For a female to be defined as having the metabolic

syndrome, she must have:

*Central obesity; defined as a waist

circumference� 80 cm{

plus any two of the following four factors

*Raised fasting plasma glucose:� 5.6 mmol/l or

previously diagnosed type 2 diabetes

*Raised triglyceride level:�1.7 mmol/l or specific

treatment for this lipid abnormality

*Reduced HDL cholesterol5 1.3 mmol/l or specific

treatment for this lipid abnormality

*Raised blood pressure: systolic�130 or diastolic

�85 mmHg, or treatment of previously

diagnosed hypertension

*, Individual manifestations of the metabolic syndrome are referred to

as MS components in the text; {, for European women

HDL, high density lipoprotein

Figure 1 Study design. NATURAL, women with reproductive status not affected by surgical or hormone therapy; REPRO, reproductive, women

with regular menstrual cycles and time since their latest menstruation 533 days; POSTm, postmenopausal, naturally postmenopausal women

with time since their last menstruation 4365 days

Metabolic syndrome and insulin resistance Lejskova et al.

84 Climacteric

Clim

acte

ric

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/28/

14Fo

r pe

rson

al u

se o

nly.

(Table 1)22. Each definition of MS reflects its multifaceted nature

in such a way that a diagnosis of MS is established whenever the

number of several components (most often, three) of

a predefined number (most often, five) of metabolic abnormal-

ities is exceeded. Hence, in each population, there are a number

of individuals who have already exceeded the limit of one or two

MS components but the number is still not sufficient to establish

the diagnosis of MS. In our study, this incidence of manifesta-

tions was referred to as ‘non-MS’ (isolated manifestations). So,

for example, non-MS for HDL cholesterol included women with

HDL cholesterol51.3 mmol/l, not meeting the diagnosis of

MS. Similarly, cases in which the criteria for the diagnosis of MS

were met were referred to as ‘at-MS’ (clustered manifestations),

e.g. at-MS for HDL cholesterol included women with HDL

cholesterol51.3 mmol/l meeting criteria of the diagnosis of

MS. Using this, the percent incidence of each component was

divided into non-MS incidence (isolated manifestations) and at-

MS incidence (clustered manifestations).

Data collection

A physician-completed questionnaire including each partici-

pant’s medical history and treatment of hypertension,

hyperlipidemia and diabetes was obtained. The physician

entered details regarding all prescribed treatments, a thorough

gynecological history, and the interval since the latest

menstrual bleeding.

Body weight, height, and waist circumference were mea-

sured with an accuracy of 0.1 kg and 0.5 cm, respectively,

according to the WHO MONICA (MONitoring trends and

determinants in CArdiovascular disease) protocol23. The

waist-to-hip ratio and the body mass index (BMI, body

weight (kg) divided by the square of body height (m)) were

calculated. Systolic and diastolic blood pressures were

measured after at least a 30-min rest in the outpatient clinic,

with the participant in the sitting position, and taking the

measurements on her right arm at heart level. The mean of the

second and third measurements of three consecutive readings

was used for analyses.

Blood samples were taken after an overnight fast. Fasting

glucose and insulin were used to calculate the index of insulin

resistance (Homeostasis Model Assessment of Insulin Resis-

tance, HOMA-IR¼ [glucose (mmol/l)6 insulin (mU/l)]/22.5).

Total serum cholesterol and triglyceride levels were measured

automatically by an enzymatic method. HDL cholesterol was

determined by the same method using kits after precipitation

of serum lipoproteins in the presence of sodium phosphotung-

state and magnesium chloride. FSH was measured using

IRMA kits (Immunotech, Prague, Czech Republic).

Statistical methods

The group characteristic gives the means with standard

deviations for continuous variables with normal distribution

verified using the F test. Statistical analysis was performed

using the two-sided, two-sample t test or the Mann–Whitney

test, and a comparison of population probabilities. The w2 test

was used in a number of cases to assess the significance of

other differences in the frequencies among groups and

subgroups. Differences in HOMA-IR were additionally

evaluated using the Kolgomorov–Smirnov and Kuiper

tests24,25.

RESULTS

Baseline characteristics

In this study, only women in the naturally reproductive stage

(REPRO, n¼ 245) were compared with naturally postmeno-

pausal women (POSTm, n¼ 149) (Figure 1). As expected,

both subgroups differed significantly in the incidence of MS

(p¼ 0.001), waist circumference and triglyceride levels

(Table 2). The levels of the other MS components did not

differ (fasting glucose, systolic and diastolic blood pressures,

HDL cholesterol), with changes in the incidence of these

components not reaching more than borderline significance.

The level of insulin resistance did not differ in the two groups,

as determined using HOMA-IR (Mann–Whitney test,

p¼ 0.156).

Analysis of changes in HOMA-IR

The MS is known to be associated primarily with the highest

HOMA-IR quartile; therefore, we were looking for differences

in the distribution of HOMA-IR that could explain the

discrepancy between HOMA-IR and the doubling of the

incidence of MS. We added the Kolgomorov–Smirnov test

(p¼ 0.064), but a difference of borderline significance in

HOMA-IR (p¼ 0.05) between the reproductive and post-

menopausal groups was only demonstrated by the Kuiper

test, which is more sensitive to differences in tails.

Differences in the distributions of both groups were clearly

documented when comparing the limits of HOMA-IR deciles

(Figure 2, Table 3): while the limits of the reproductive and

postmenopausal groups were virtually identical in the lower

four deciles, the differences between the two groups tended

to increase in the higher deciles, being the source for the

outcome of the Kuiper test. HOMA-IR was compared

separately in both subgroups of women with a low

HOMA-IR (lower five deciles – below the median; not

significant) and in both subgroups of women with a high

HOMA-IR (upper five deciles – above the median; Mann–

Whitney test, p¼ 0.0004).

Menopausal status and MS

An increase in the incidence of MS was seen only in women

with a high HOMA-IR (Figure 3, Table 4). Both subgroups of

women with low, non-rising HOMA-IR levels showed a low


Climacteric 85

Clim

acte

ric

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/28/

14Fo

r pe

rson

al u

se o

nly.

incidence of MS, not increasing in menopause (p¼ 0.2).

Women with high HOMA-IR levels, which increased in

menopause (1.8–2.1), showed a high incidence of MS, which

almost doubled during menopause (REPRO 30.9%, POSTm

57.3%; p5 0.00001).

Menopausal status and clustering of MS components

We sought to determine not only the incidence of MS (clustered

components) but, also, the incidence of ‘isolated’ components in

women without MS showing at least one of the four variable MS

components, i.e. in addition to waist circumference, being

conditio sine qua non in the IDF definition. Each of the MS

components is known to be associated with HOMA-IR;

consistent with this fact, we demonstrated that the proportions

of women with any MS component(s) were higher in both

subgroups with high HOMA-IR (low HOMA-IR: REPRO

44.7%, POSTm 50.7%; high HOMA-IR: REPRO 78.0%,

POSTm 86.7%).

In the postmenopausal subgroup with a high HOMA-IR,

there was an increase in the incidence of clustered components

diagnostic of MS at the expense of isolated components (w2;

p50.001; Figure 3, Table 4). A possible interpretation of this

result is that a reproductive woman with a high HOMA-IR

and an isolated component is most likely to present (an)other

component(s) of MS during menopause, thus meeting the

criteria for MS.

We also investigated the effect of menopause on the

clustering of MS components for each of the five components

separately (Figure 4, Table 5). With each individual MS

component, we found the same changes as with overall

incidences. In the group of postmenopausal women, the

clustered incidence tended to rise at the expense of isolated

incidence, i.e. the ratio of clustered to isolated incidence was

higher in postmenopausal women compared with reproduc-

tive ones. The most marked increase (by a factor of 3.4) in the

ratio was seen for HDL cholesterol, whose average levels were

identical in the group characteristics of reproductive and

postmenopausal women.

Table 2 Characteristics and comparison of the reproductive and postmenopausal groups. Data are given as mean+ standard deviation

Enrolled

(n¼862)

REPRO

(n¼245)

POSTm

(n¼149)

REPRO/

POSTm p Value

Age (years) 50.0+2.7 48.3+ 2.3 52.2+ 2.0 50.0001*

Age at the last menstruation (years) 47.8+4.0 48.2+ 2.3 47.8+ 3.7 ns{

Time since the last menstruation (months) 27+48 0.43+ 0.26 52+ 38 50.0001*

Follicle stimulating hormone (U/l) 42.3+38.6 16.5+ 18.9 81.0+ 33.8 50.0001*

Continuous variables

Waist circumference (cm) 86.7+12.4 85.1+ 10.8 90.9+ 13.8 50.0001*

Body mass index (kg/m2) 26.0+4.9 25.6+ 4.2 27.3+ 5.8 50.01*

Fasting plasma glucose (mmol/l) 5.23+1.01 5.17+ 1.01 5.41+ 1.47 ns*

Fasting plasma insulin (IU/ml) 6.6+3.9 6.4+ 3.7 6.8+ 3.8 ns{

HOMA-IR 1.57+1.22 1.48+ 0.92 1.74+ 1.72 ns*

Total cholesterol (mmol/l) 5.6+0.9 5.4+ 0.9 5.9+ 0.9 50.0001*

Triglycerides (mmol/l) 1.34+0.74 1.28+ 0.65 1.58+ 0.95 50.001{

HDL cholesterol (mmol/l) 1.64+0.39 1.59+ 0.36 1.60+ 0.39 ns*

LDL cholesterol (mmol/l) 3.41+0.86 3.34+ 0.80 3.69+ 0.87 50.001*

SBP (mmHg) 118.9+15.8 118.7+ 15.0 120.7+ 16.7 ns*

DBP (mmHg) 78.8+10.0 79.4+ 9.5 79.3+ 9.3 ns*

Categorical variables

IDF-defined metabolic syndrome 26.5+1.5% 22.9+ 2.6% 38.3+ 4.0% 50.001{

Waist circumference� 80 cm 68.8+1.6% 65.3+ 3.0% 76.5+ 3.5% 50.02{

Triglycerides� 1.7 mmol/l or fibrates 22.9+1.4% 19.6+ 2.5% 30.2+ 3.8% 50.02{

SBP�130 mmHg or DBP� 85 mmHg

or antihypertensive therapy

40.5+1.7% 35.9+ 3.1% 47.0+ 4.1% 50.05{

HDL cholesterol51.3 mmol/l 20.0+1.4% 19.6+ 2.5% 26.2+ 3.6% ns{

Fasting glucose� 5.6 mmol/l or

history of diabetes mellitus

22.5+1.4% 20.4+ 2.6% 30.2+ 3.8% 50.05{

Antihypertensive therapy 17.5+1.3% 12.7+ 2.1% 24.8+ 3.5% 50.01{

Enrolled, enrolled women with complete data; REPRO, reproductive women with still regular menstrual cycles and time since last menstruation

533 days; POSTm, postmenopausal women with time since last menstruation 4 365 days; HOMA-IR, Homeostasis Model Assessment of

Insulin Resistance; HDL, high density lipoprotein; LDL, low density lipoprotein; IDF, International Diabetes Federation; ns, not significant

*, t test; {, Mann–Whitney test; {, population probability test


86 Climacteric

Clim

acte

ric

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/28/

14Fo

r pe

rson

al u

se o

nly.

DISCUSSION

Changes in waist circumference

A characteristic feature of our representative population

sample of Czech women was a high rate of

visceral (abdominal) obesity, as determined by waist circum-

ference. Waist circumference also represented an MS compo-

nent showing the most appreciable deterioration during

transition to menopause, followed by triglyceride levels. Both

the increase in waist circumference and the increase in

triglyceride levels belong to manifestations of development

of an androgenic hormonal milieu during transition to

menopause4,26. Visceral obesity expressed as waist circumfer-

ence is known to be an independent risk factor of coronary

events, in particular when associated with insulin resistance

and dyslipidemia27. While the increase in waist circumference

is a marker of visceral obesity identified, in recent years, as a

primary disorder in MS, studies conducted in the 1980s and

1990s suggested the primary disorder was insulin resistance

markedly associated with MS28.

Changes in MS and HOMA-IR

In our group, menopause was followed by a doubling in the

incidence of MS without an apparent increase in the mean of

the parameter of insulin resistance, HOMA-IR. The reason for

this became clear when comparing the deciles of the HOMA-

IR of the reproductive and postmenopausal groups in more

detail (Figure 2). MS develops in individuals with the highest

insulin resistance28 and, in menopause, it was just in these

women with high HOMA-IR where an increase occurred,

whereas the limits of deciles of low HOMA-IR were virtually

identical in reproductive and postmenopausal women. Our

study thus documents that the doubling of the incidence of MS

without an obvious increase in mean HOMA-IR is consistent

with known facts, since MS develops exclusively in women

with a high HOMA-IR whose HOMA-IR tended to rise

significantly during menopause (Figures 2 and 3).

The clustering of MS components

As noted above, the subgroups showing the most marked

impact of menopause were those with the highest insulin

resistance: it was just these women who showed a dramatic

increase in the incidence of MS while the proportion of

women with isolated components decreased (Figure 3). In

those with a high HOMA-IR, there was a tripling in the ratio

of clustered/isolated MS components among the reproductive

and postmenopausal subgroups. The results of our study are

thus consistent with the concept that metabolic abnormalities

are not affected identically in all women entering the

menopausal transition. Those at highest risk include women

with an increased insulin resistance showing, additionally,

any metabolic abnormality related to MS.

Figure 2 Changes in HOMA-IR during transition to menopause by

deciles (Table 3). HOMA-IR, Homeostasis Model Assessment of

Insulin Resistance

Table 3 Changes in HOMA-IR during the menopausal transition by deciles (Figure 2)

HOMA-IR REPRO POSTm HOMA-IR

p test

Mann–Whitney

Minimum 0.11 0.27

1st decile 0.59 0.62 Low HOMA-IR 0.72

2nd decile 0.81 0.83

3rd decile 0.98 0.99

4th decile 1.18 1.17

Median (5th decile) 1.30 1.40

6th decile 1.41 1.70 High HOMA-IR 0.0004




Maximum (10th decile) 6.27 18.67

REPRO, reproductive women with still regular menstrual cycles and time since last menstruation 533 days; POSTm, postmenopausal women

with time since last menstruation 4 365 days; HOMA-IR, Homeostasis Model Assessment of Insulin Resistance


Climacteric 87

Clim

acte

ric

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/28/

14Fo

r pe

rson

al u

se o

nly.

More interesting still is the fact that some MS components

seemingly did not contribute to an increased incidence of MS

in menopause, when taking into account the significance of

changes in MS components (Table 2). However, a more

detailed analysis (Figure 4) revealed an increase in the ratio of

clustered to isolated components, with all components during

menopause. The implications are that clustered incidence

increases at the expense of isolated incidence with all

components, and that it is just this mechanism whereby each

component contributes to the increased incidence of MS. The

described changes are the most marked with HDL cholesterol

where reproductive and postmenopausal women show iden-

tical total means and a similar percent incidence rates of the

component. Menopause was associated with a significant

increase in the proportion of women with low HDL

cholesterol as part of the diagnosis of MS (clustered: REPRO

11%, POSTm 21%) and a decrease in women with isolated

low HDL cholesterol (isolated: REPRO 9%, POSTm 5%).

Consequently, low HDL cholesterol is thus ‘shifted’, during

menopause, to women with MS. This finding is consistent

with the concept that the menopausal transition is associated

with the manifestation of (an)other component(s) of MS,

primarily in women at risk of developing MS, with at least one

isolated MS component present already in their reproductive

age.

The described mechanism results in a decrease in the

proportion of isolated components and an increase in the

proportion of clustered ones, while there is an increase in the

incidence of MS; all this can be seen primarily in women with

a higher HOMA-IR. Judging by our results, it is these women

with a high HOMA-IR and at least one MS component

present who are at considerable risk for developing MS during

the menopausal transition and, hence, having also a higher

cardiovascular risk compared with women not meeting these

preconditions.

Clinical significance

There is evidence that the increase in total body weight in

menopause is associated with a decrease in the proportion of

lean body weight, and the increase in central obesity during

menopause is a well-known fact26,29,30. Recent studies have

Figure 3 The incidence of the metabolic syndrome (MS), i.e. clustered manifestations of the metabolic syndrome accelerate in menopause in the

presence of high HOMA-IR at the expense of isolated manifestations (Table 4). non-MS, incidence of any components without the metabolic

syndrome; at-MS, incidence of metabolic syndrome (incidence of any components which are associated with the metabolic syndrome); HOMA-

IR, Homeostasis Model Assessment of Insulin Resistance

Table 4 Clustered manifestations of the metabolic syndrome(MS)

postmenopausally increase in the presence of high HOMA-IR at the

expense of isolated manifestations (Figure 3)

Proportion of women

with manifestations

of MS

REPRO

(n¼245)

POSTm

(n¼149)

p Value

w2 test

Low HOMA-IR n¼122 n¼ 74

Non-MS 30.9% 32.0% ns

At-MS (¼incidence of MS) 13.8% 18.7%

Ratio At-MS/Non-MS 0.45 0.58

High HOMA-IR n¼122 n¼ 74

Non-MS 47.2% 29.3% p5 0.001

At-MS (¼ incidence of MS) 30.9% 57.3%

Ratio At-MS/Non-MS 0.66 1.95

Non-MS, incidence of a component without the metabolic syndrome;

At-MS, incidence of a component associated with the metabolic

syndrome; REPRO, reproductive women with still regular menstrual

cyc le s and t ime s ince las t mens truat ion 533 days ;

POSTm, postmenopausal women with time since last menstruation

4365 days; HOMA-IR, Homeostasis Model Assessment of Insulin

Resistance


88 Climacteric

Clim

acte

ric

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/28/

14Fo

r pe

rson

al u

se o

nly.

Table 5 Clustering of individual components of the metabolic syndrome (MS) (Figure 4)

Proportion of women with incidence of MS components

REPRO

(n¼ 245)

POSTm

(n¼149)

p Value

w2 test

Waist circumference� 80 cm

Non-MS for waist circumference 43.3% 38.3% 0.011

At-MS for waist circumference 22.0% 38.3%

Ratio At-MS/Non-MS for waist 0.5 1.0

Triglycerides� 1.7 mmol/l or fibrates therapy

Non-MS for triglycerides 4.9% 5.4% 0.4

At-MS for triglycerides 14.7% 24.8%

Ratio At-MS/Non-MS for triglycerides 3.0 4.6

SBP�130 or DBP�85 mmHg or antihypertensive therapy

Non-MS for blood pressure 19.2% 15.4% 0.016

At-MS for blood pressure 16.7% 31.5%

Ratio At-MS/Non-MS for blood pressure 0.9 2.0

Fasting glucose� 5.6 mmol/l or history of diabetes mellitus

Non-MS for glucose 8.2% 7.4% 0.17

At-MS for glucose 12.2% 22.8%

Ratio At-MS/Non-MS for glucose 1.4 3.1

HDL cholesterol5 1.3 mmol/l

Non-MS for HDL cholesterol 8.6% 4.7% 0.010

At-MS for HDL cholesterol 11.0% 21.5%

Ratio At-MS/Non-MS for HDL cholesterol 1.3 4.6

Non-MS, incidence of a component without the metabolic syndrome; At-MS, incidence of a component associated with the metabolic

syndrome; REPRO, reproductive women with still regular menstrual cycles and time since last menstruation 533 days; POSTm,

postmenopausal women with time since last menstruation 4365 days; HOMA-IR, Homeostasis Model Assessment of Insulin Resistance;

HDL, high density lipoprotein

Figure 4 Clustering of manifestations of the metabolic syndrome (MS) in menopause rises with each of the components of the metabolic

syndrome (Table 5). The metabolic syndrome components are as defined in Table 1. WAIST, waist circumference; BP, blood pressure; TG,

triglycerides; HDL-C, high density lipoprotein cholesterol


Climacteric 89

Clim

acte

ric

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/28/

14Fo

r pe

rson

al u

se o

nly.

suggested that these changes are elicited by the decrease in the

effect of estrogens, which is accompanied by a relative

increase in the effect of androgens during the menopausal

transition4,5, and that the incidence of MS tends to rise even

after adjustment to age, BMI and smoking status31,32.

However, a large epidemiological study (9097 women in the

Chinese rural population) reported even a mild decrease in

body weight and BMI (from 22.5 to 22.0 kg/m2) in

menopause. Despite the huge size of the series, no significant

changes were observed in waist circumference, waist-to-hip

ratio, fasting glucose and insulin, HOMA-IR, diastolic blood

pressure, body fat percent and even in the incidence of MS

following adjustments33.

The above results suggest there may be considerable

differences in the metabolic impacts of menopause, and that

these differences may be based on the variability of the

metabolic profile of the populations studied. The above study

showed that, under certain circumstances, the effect of

menopause on the incidence of MS need not be as adverse

as that seen in our Czech population. Our data may be

different not only due to genetic differences but, also, due to

differences in lifestyle. Our analysis of the relationship

between HOMA-IR and changes in MS showed that the

incidence of MS was not increasing in women with low

HOMA-IR. By contrast, women with high HOMA-IR are at

risk of a doubled incidence of MS.

To the best of our knowledge, ours is the first study

explaining the appreciable rise in the incidence of MS in the

presence of non-significant changes in the means of MS

components and average insulin resistance. The aims of our

study were achieved using a 5% representative population

sample without major ethnic differences and within a

narrow age range, with a limitation to interpreting the

results being the cross-sectional nature of the study. This is

the first study analyzing changes in the ratios of incidence

of clustered and isolated manifestations of MS and using

these changes to explain the rising incidence of MS in the

presence of seemingly non-significant changes in a number

of components.

CONCLUSION

Transition to menopause brings about an increase in

cardiovascular risk associated with manifestations of MS.

While, overall, the most marked increase can be seen in

visceral obesity, as determined by waist circumference and

triglyceride levels, changes in the other components also

contribute to the increased incidence of MS. The index of

insulin resistance (HOMA-IR) may rise, during the meno-

pause transition, only in the highest values, where it is

associated with accelerated clustering of MS components. The

results of our study show that women entering menopause

with isolated components of MS are at high risk of MS

manifesting and are those at whom prevention of MS should

be targeted.

Conflict of interest Nil.

Source of funding Supported by research grants NA7512-

3/2005 and NS10511-3/2009 of IGA MH CR (Grant Agency

of the Ministry of Health of the Czech Republic).

References

1. Rosamond W, Flegal K, Furie K, et al. American HeartAssociation Statistics Committee and Stroke Statistics Subcom-

mittee. Heart disease and stroke statistics – 2007 update: a

report from the American Heart Association Statistics Commit-

tee and Stroke Statistics Subcommittee. Circulation 2007;115:9–171

2. World Health Organization Statistical Information system. 2007.

Available at: www.who.int/whosis/. Accessed November 26,

20093. Lorenzo C, Williams K, Hunt KJ, Haffner SM. The National

Cholesterol Education Program – Adult Treatment Panel III,

International Diabetes Federation, and World Health Organiza-

tion definitions of the metabolic syndrome as predictors ofincident cardiovascular disease and diabetes. Diabetes Care2007;30:8–13

4. Janssen I, Powell LH, Crawford S, et al. Menopause and themetabolic syndrome: the Study of Women’s Health Across the

Nation. Arch Intern Med 2008;168:1568–75

5. Torrens JI, Sutton-Tyrrell K, Zhao X, et al. Relative

androgen excess during the menopausal transition predictsincident metabolic syndrome in midlife women: Study of

Women’s Health Across the Nation. Menopause 2009;16:257–

64

6. Weinberg ME, Manson JE, Buring JE, et al. Low sex hormone-binding globulin is associated with the metabolic syndrome in

postmenopausal women. Metabolism 2006;55:1473–80

7. Mesch VR, Siseles NO, Maidana PN, et al. Androgens in

relationship to cardiovascular risk factors in the menopausaltransition. Climacteric 2008;11:509–17

8. Carr MC. The emergence of the metabolic syndrome

with menopause. J Clin Endocrinol Metab 2003;88:2404–11

9. Cifkova R, Pitha J, Lejskova M, et al. Blood pressure around themenopause: a population study. J Hypertens 2008;26:1976–82

10. Piche ME, Lapointe A, Weisnagel SJ, et al. Regional body fat

distribution and metabolic profile in postmenopausal women.

Metabolism 2008;57:1101–711. DeNino WF, Tchernof A, Dionne IJ, et al. Contribution of

abdominal adiposity to age-related differences in insulin sensitiv-

ity and plasma lipids in healthy nonobese women. Diabetes Care2001;24:925–32

12. Toth MJ, Sites CK, Eltabbakh GH, Poehlman ET. Effect

of menopausal status on insulin-stimulated glucose

disposal: comparison of middle-aged premenopausal and earlypostmenopausal women. Diabetes Care 2000;23:801–6

13. Qader SS, Shakir YA, Nyberg P, et al. Sociodemographic risk

factors of metabolic syndrome in middle-aged women: results from


90 Climacteric

Clim

acte

ric

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/28/

14Fo

r pe

rson

al u

se o

nly.

http://www.who.int/whosis/

a population-based study of Swedish women, The Women’s Health

in the Lund Area (WHILA) Study. Climacteric 2008;11: 475–82

14. Evolahti A, Hultcrantz M, Collins A. Psychosocialwork environment and lifestyle as related to lipid profiles in

perimenopausal women. Climacteric 2009;12:131–45

15. Villa P, Sagnella F, Perri C, et al. Low- and standard-estrogen

dosage in oral therapy: dose-dependent effects on insulin and lipidmetabolism in healthy postmenopausal women. Climacteric2008;11:498–508

16. Gupta P, Harte A, Sturdee DW, et al. Effects of menopausal status

on circulating calcitonin gene-related peptide and adipokines:implications for insulin resistance and cardiovascular risks.

Climacteric 2008;11:364–72

17. Koga M, Saito H, Mukai M, et al. Factors contributing

to increased serum urate in postmenopausal Japanese females.Climacteric 2009;12:146–52

18. Dupuy AM, Carriere I, Scali J, et al. Lipid levels and

cardiovascular risk in elderly women: a general population studyof the effects of hormonal treatment and lipid-lowering agents.

Climacteric 2008;11:74–83

19. Molarius A, Seidell JC, Sans S, et al. Waist and hip circumferences,

and waist-hip ratio in 19 populations of the WHO MONICAProject. Int J Obes Relat Metab Disord 1999;23:116–25

20. Soules MR, Sherman S, Parrott E, et al. Executive summary:

Stages of Reproductive Aging Workshop (STRAW). Climacteric2001;4:267–72

21. Harlow SD, Crawford S, Dennerstein L, et al. Recommendations

from a multi-study evaluation of proposed criteria for staging

reproductive aging. Climacteric 2007;10:112–1922. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome – a new

world-wide definition. A Consensus Statement from the Interna-

tional Diabetes Federation. Diabet Med 2006;23:469–80

23. Meisinger C, Thorand B, Schneider A, et al. Sex differences in risk

factors for incident type 2 diabetes mellitus. The MONICA

Augsburg Cohort Study. Arch Intern Med 2002;162:82–924. Kolmogorov–Smirnov test from Wikipedia. Available at: http://

en.wikipedia.org/wiki/Kolmogorov%E2%80%93Smirnov_test.

Accessed November 26, 2009

25. Kuiper’s test from Wikipedia. Available at: http://en.wikipe-dia.org/wiki/Kuiper’s_test. Accessed November 26, 2009

26. Ferrara CM, Lynch NA, Nicklas BJ, et al. Differences in adipose

tissue metabolism between postmenopausal and perimenopausal

women. J Clin Endocrinol Metab 2002;87:4166–7027. Carr MC, Brunzell JD. Abdominal obesity and dyslipidemia in the

metabolic syndrome: importance of type 2 diabetes and familial

combined hyperlipidemia in coronary artery disease risk. J ClinEndocrinol Metab 2004;89:2601–7

28. Reaven GM. Banting lecture 1988. Role of insulin resistance in

human disease. Diabetes 1988;37:1595–607

29. Sowers M, Zheng H, Tomey K, et al. Changes in body compositionin women over six years at midlife: ovarian and chronological

aging. J Clin Endocrinol Metab 2007;92:895–901

30. Tchernof A, Desmeules A, Richard C, et al. Ovarian hormone

status and abdominal visceral adipose tissue metabolism. J ClinEndocrinol Metab 2004;89:3425–30

31. Petri Nahas EA, Padoani NP, Nahas-Neto J, et al. Metabolic

syndrome and its associated risk factors in Brazilian postmeno-

pausal women. Climacteric 2009;12:431–832. Mesch VR, Boero LE, Siseles NO, et al. Metabolic syndrome

throughout the menopausal transition: influence of age and

menopausal status. Climacteric 2006;9:40–833. Feng Y, Hong X, Wilker E, et al. Effects of age at menarche,

reproductive years, and menopause on metabolic risk factors for

cardiovascular diseases. Atherosclerosis 2008;196:590–7


Climacteric 91

Clim

acte

ric

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

onne

ctic

ut o

n 10

/28/

14Fo

r pe

rson

al u

se o

nly.

http://en.wikipedia.org/wiki/Kolmogorov%E2%80%93Smirnov_test

http://en.wikipedia.org/wiki/Kolmogorov%E2%80%93Smirnov_test

http://en.wikipedia.org/wiki/Kuiper's_test

http://en.wikipedia.org/wiki/Kuiper's_test

menopause: clustering of metabolic syndrome components and population changes in insulin resistance

Documents